Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
UCB Pharma S.A., Product Development, B-1420, Braine l'Alleud, Belgium.
AAPS J. 2022 Jan 10;24(1):26. doi: 10.1208/s12248-021-00661-2.
This study aimed to explore the potential of biopharmaceutics in vitro tools to predict drug product performance in the pediatric population. Biorelevant dissolution set-ups were used to predict how age and medicine administration practices affect the in vitro dissolution of oral formulations of a poorly water-soluble compound, montelukast. Biorelevant age-appropriate dissolution studies of Singulair (granules and chewable tablets) were conducted with the µDISS profiler™, USP 4 apparatus, USP 2 apparatus, and mini-paddle apparatus. Biorelevant simulating fluids representative of adult and pediatric conditions were used in the dissolution studies. The biorelevant dissolution conditions were appropriately selected (i.e. volumes, transit times, etc.) to mimic the gastrointestinal conditions of each of the subpopulations tested. Partial least squares regression (PLS-R) was performed to understand the impact of in vitro variables on the dissolution of montelukast. Montelukast dissolution was significantly affected by the in vitro hydrodynamics used to perform the dissolution tests (µDISS profiler™: positive effect); choice of simulation of gastric (negative effect) and/or intestinal conditions (positive effect) of the gastrointestinal tract; and simulation of prandial state (fasted state: negative effect, fed state: positive effect). Age-related biorelevant dissolution of Singulair granules predicted the in vivo effect of the co-administration of the formulation with applesauce and formula in infants. This study demonstrates that age-appropriate biorelevant dissolution testing can be a valuable tool for the assessment of drug performance in the pediatric population.
本研究旨在探讨生物药剂学体外工具在预测儿科人群药物产品性能方面的潜力。使用生物相关溶解装置来预测年龄和用药实践如何影响一种水溶性差的化合物孟鲁司特的口服制剂的体外溶解。使用 µDISS profiler™、USP4 装置、USP2 装置和迷你桨板装置对 Singulair（颗粒剂和咀嚼片）进行了生物相关的适合年龄的溶解研究。在溶解研究中使用了代表成人和儿科条件的生物相关模拟液。生物相关的溶解条件经过适当选择（即体积、传输时间等），以模拟每个测试亚群的胃肠道条件。偏最小二乘回归（PLS-R）用于理解体外变量对孟鲁司特溶解的影响。孟鲁司特的溶解受到用于进行溶解测试的体外流体动力学的显著影响（µDISS profiler™：正效应）；胃模拟选择（负面效应）和/或肠道条件模拟（正面效应）的选择；以及模拟进食状态（禁食状态：负面效应，进食状态：正面效应）。Singulair 颗粒剂的年龄相关生物相关溶解预测了该制剂与苹果酱和配方同时给药在婴儿体内的效果。本研究表明，适合年龄的生物相关溶解测试可以成为评估儿科人群药物性能的有价值工具。
